PGx Lecture 5

Question 1

Does S- or R-Warfarin exhibit more activity

Answer 1

S-Warfarin

Question 2

MOA of Warfarin (simplified)

Answer 2

inhibits synthesis of Vitamin K dependent coagulation factors

Question 3

Problems with Warfarin

Answer 3

• narrrow TI
• large interpatient variability
• very difficult to dose correctly

Question 4

Too much warfarin leads to _______, while too little leads to__________

Answer 4

excess bleeding; blood-clot formation

Question 5

What is INR

Answer 5

International Normalized Ratio

Question 6

What does INR measure used for

Answer 6

to determine the clotting tendency of blood; monitor and adjust warfarin dose based on INR

Question 7

Factors for variable warfarin response

Answer 7

• extrinsic factors (DDI, drug-diet interaction)
• intrinsic factors (age, gender, weight)
• genetic factors (polymorphisms)

Question 8

What is the INR target for warfarin

Answer 8

2-3

Question 9

CYP2C9 is a pharmacodynamic or kinetic allele

Answer 9

Pharmacokinetic

Question 10

VKORC1 is a pharmacodyamic or kinetic allele

Answer 10

pharmakodynamic

Question 11

To major drugs metabolized by CYP2C9

Answer 11

s-warfarin

phenytoin

Question 12

Two major non-synonymous SNPs of CYP2C9

Answer 12

CYP2C92 (18% activity)
CYP2C93 (5% activity)
both have reduced function but 3 is more reduced than 2

Question 13

CYP2C9 genotypes PM of warfarin

Answer 13

3/3
3/2
2/2

Question 14

CYP2C9 genotypes EM of warfarin

Answer 14

3/1
2/1
1/1

Question 15

maintenance dose of warfarin is significantly related to

Answer 15

functional CYP2C9 alleles

Question 16

PM for CYP2C9 require higher or lower dose of warfarin

Answer 16

LOWER

Question 17

S-warfarin ADR in PM

Answer 17

prolonged bleeding, lower dose to achieve optimum anticoag activity

Question 18

Phenytoin ADR in PM

Answer 18

OD: ataxia, mental confusion, disturbances of consciousness

Question 19

What is VKORC1

Answer 19

Vitamin K reductase complex 1. Major target for warfarin

Question 20

What does VKORC1 do

Answer 20

converts inactive epoxide form of vitamin K into active, reduced vitamin K

Question 21

what is responsible for individual variability in dosing

Answer 21

polymorphisms of VKORC1

Question 22

In the face of reduced VKORC1, more/less warfarin is required to elicit an effect

Answer 22

LESS

Question 23

what clotting factors is Vit K essential fo

Answer 23

II, VII, IX, X

Question 24

SNPs or Haplotypes of the VKORC1 gene have been associated with higher/lower enzymatic activity and higher/lower dose requirements in the maintenance dose for warfarin

Answer 24

LOWER; LOWER

Question 25

Promoter SNP in VKORC1

Answer 25

G-1639A

Question 26

Does the promoter SNP in VKORC1 result in increased or decreased transcription

Answer 26

DECREASED

Question 27

The A allele alters VKORC1 transcription factor binding site and leads to higher/lower protein expression

Answer 27

LOWER

Question 28

Heterozygotes GA and homozygotes AA requires higher/lower dose of warfarin compared to homozygotes GG

Answer 28

LOWER

Question 29

S-warfarin is mainly metablized to _______ by ________

Answer 29

7-hydroxywarfarin (inactive);

CYP2C9

Question 30

metabolism of warfarin affects

Answer 30

PK

Question 31

inhibition of VKORC1 activity affects

Answer 31

PD

Question 32

In addition to genetic markers, what helps predict warfarin dose

Answer 32

age, sex, weight, height, smoking status, genotypes